The Sarkis Mazmanian Lab - Caltech Biology

We All Live In a Microbial World

Reflecting a growing medical crisis in Western societies, recent epidemiologic and clinical reports have revealed dramatic increases in the incidences of several immune disorders: inflammatory bowel disease, asthma, type 1 diabetes, and multiple sclerosis. The hygiene hypothesis proposed almost three decades ago speculated that these increases are the result of lifestyle changes and medical advances that reduce exposure to microbial pathogens. Microbial infections are, in fact, rare and opportunistic. In contrast, mammals are colonized for life with 100 trillion bacterial cells consisting of hundreds of microbial species, and the contributions of this enormous and diverse ecosystem to human health remain poorly understood.

Recent studies have launched a revolution in biology aimed at understanding how (and more importantly, why) mammals harbor multitudes of symbiotic bacteria. Our laboratory demonstrated for the first time the specific gut bacteria direct the development of the mammalian immune system and confer protection from intestinal diseases; thus fundamental aspects of health are absolutely dependent o microbial symbiosis. Astonishingly, the disorders whose incidences are increasing in Western countries involve a common immunologic defect found in the absence of intestinal bacteria. After eons of co-evolution with our microbial partners, have societal advances (including sanitation, 'western' diets, and antibiotics) paradoxically affected human health adversely by reducing our exposure to health-promoting bacteria?

We propose that the human genome does not encode all functions required for health, but rather that humans depend on crucial interactions with products of the microbiome (the collective genomes of our intestinal bacterial species). Advances in the past few years now make it possible to mine this untapped reservoir for beneficial microbial molecules. Using advanced genomic, microbiologic, immunologic methods and animal models, our goal is to define the molecular processes evolved by symbiotic bacteria that mediate protection from inflammatory and autoimmune diseases. An understanding of the beneficial immune responses promoted by symbiotic gut bacteria may lead to the development of natural therapeutics based on entirely novel biological principles.